Multiple sclerosis (MS) is considered as an autoimmune disease of the central nervous system. This disease manifests diverse neurological symptoms such as motor paralysis, sensory impairment, higher brain dysfunction, visual loss, and dysuria due to infiltration of autoreactive lymphocytes (mainly, T cells or B cells) into the brain, the spinal cord, or the optic nerve, causing inflammations targeting perineural myelin proteins. Approximately a million people are presumed to suffer from this disease worldwide. Particularly, in Western countries, MS is highly prevalent and is known as a typical neurological disease for young adults. Although the disease had been thought to be less common in Asian countries, abrupt increase in its prevalence has been reported in Japan in recent years (Non Patent Literature 1). This strongly suggests the involvement of not only genetic factors but environmental factors in the occurrence of MS, and is also presenting problems in that neurological symptoms remaining as sequelae result in breakdown of family life and social life including occupations. The great majority of MS patients develop transient and repetitive inflammations at various sites of the central nervous system. As each inflammation occurs, neurological symptoms are manifested depending on the inflammation site. This clinical event is called “relapse”, and the course of recurrence is referred to as “relapsing-remitting (RR)”. In relapsing-remitting MS (RRMS), sequelae accumulate with each relapse, leading to increasing deterioration of the activities of daily living (ADL). When the affected period becomes longer, more cases move on to secondary progressive (SP) MS, in which neurological symptoms gradually progress without relapses. At this stage, the great majority of cases already have moderate fixed neurological disability. Thus, treatment from an earlier stage, i.e. the RRMS stage, is believed to be important.
Recombinant interferon beta (IFN-β) has been used as the first line therapy to prevent relapses of RRMS, and is reported to be effective for suppressing the relapses and also effective for suppressing progression in the degree of impairment. In Japan, Avonex (registered trademark) (interferon beta-1a) and Betaferon (registered trademark) (interferon beta-1b) are used. However, their administration becomes difficult to continue in many patients due to manifestation of serious adverse reactions (interstitial pneumonia, autoimmune hepatitis, thyroid dysfunction, skin ulcer, psychological symptoms such as depression, leukopenia, etc.), or due to aggravation of latent immune disorders (collagen disease, thyroiditis, etc.) the patients may have originating from autoimmune abnormalities. Also, it has been reported that 30 to 50% of the patient population who may continue administration are resistant cases which show no therapeutic effect or result in aggravation of symptoms. These facts imply that RRMS includes a subgroup where administration of IFN-β should be avoided, while it is difficult to predict patients to whom IFN-β is not applicable (IFN-β-nonresponsive patients) before administration of IFN-β.
For patients to whom IFN-β is not applicable, the process of assessing whether IFN-β is applicable accompanies great suffering. Specifically, in cases where administration is discontinued due to serious adverse reaction or aggravation of concomitant immune disorder, the fact that IFN-β is not applicable is not known until administration of IFN-β is attempted and these events manifest. Even when administration can be continued, a length of treatment of at least half a year to 1 year is required for determining its therapeutic effect. Since the mode of administration of IFN-β preparations is self-injection (intramuscular injection or subcutaneous injection), this administration is painful and, in addition, the patients must endure adverse reactions such as influenza-like symptoms and headaches, which, while not leading to discontinuation of the administration, require some additional treatments.
Thus, there has been a strong demand for development of a method for predicting the therapeutic effect of IFN-β, the manifestation of a serious adverse reaction, and the aggravation of concomitant immune disorder before the start of treatment in order to avoid painful, unnecessary medication for patients to whom IFN-β is not applicable and to appropriately select applicable patients. In addition, the patients to whom IFN-β is not applicable are often difficult to treat even with other drugs. Thus, it has also been required to establish a novel treatment method.
Previously, a method which involves measuring the expression level of a particular gene group in leukocytes derived from the peripheral blood of a patient by use of a DNA chip or the like has been reported as a method for predicting the therapeutic effect of IFN-β on RRMS (Patent Literature 1).
Plasmablasts (PBs) are a subset of B cells, a type of lymphocytes, and have the specialized function of producing antibodies. In neuromyelitis optica (NMO), an autoimmune disease of the central nervous system the distinction of which from MS is clinically important despite its pathology different from MS, PBs have been identified as a source of production of anti-aquaporin 4 antibody (anti-AQP4 antibody), which is an autoantibody deeply involved in the pathogenesis of NMO, and have been reported to be increased in the peripheral blood of NMO patients (Non Patent Literature 2). The survival of NMO patient-derived PBs and their ability to produce the anti-AQP4 antibody are also known to be promoted in a manner dependent on interleukin 6 (IL-6) (Non Patent Literature 2). It has been reported so far that typical RRMS patients have a peripheral blood PB frequency equivalent to that of healthy persons (Non Patent Literature 2), and that SPMS patients show an increase of PBs in the peripheral blood (Non Patent Literature 3). A previous pathological study of MS brain lesions has suggested the involvement of an autoantibody in the formation of the lesions (Non Patent Literature 4). Recently, the presence of a disease-specific autoantibody in the serum of MS (including RRMS) patients has been reported (Non Patent Literature 5).
Furthermore, it has been reported that the therapeutic effect of an IL-6 inhibitor is high on patients with RRMS in which PBs occur at high levels, and that the therapeutic effect of an IL-6 inhibitor on RRMS can be predicted using the amount of PBs derived from RRMS patients as an indicator (Patent Literature 2). However, further establishment of a highly accurate and effective prediction method is desired.